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. 2023 Feb 17;13(4):2240-2249.
doi: 10.1021/acscatal.2c05484. Epub 2023 Jan 27.

Mechanism of a Dually Catalyzed Enantioselective Oxa-Pictet-Spengler Reaction and the Development of a Stereodivergent Variant

Alafate Adili  1 , John-Paul Webster  2 , Chenfei Zhao  3 , Sharath Chandra Mallojjala  2 , Moises A Romero-Reyes  1 , Ion Ghiviriga  4 , Khalil A Abboud  5 , Mathew J Vetticatt  2 , Daniel Seidel  6
Affiliations

Mechanism of a Dually Catalyzed Enantioselective Oxa-Pictet-Spengler Reaction and the Development of a Stereodivergent Variant

Alafate Adili et al. ACS Catal. .

Abstract

Enantioselective oxa-Pictet-Spengler reactions of tryptophol with aldehydes proceed under weakly acidic conditions utilizing a combination of two catalysts, an indoline HCl salt and a bisthiourea compound. Mechanistic investigations revealed the roles of both catalysts and confirmed the involvement of oxocarbenium ion intermediates, ruling out alternative scenarios. A stereochemical model was derived from density functional theory calculations, which provided the basis for the development of a highly enantioselective stereodivergent variant with racemic tryptophol derivatives.

Keywords: DFT calculations; anion-binding catalysis; asymmetric catalysis; dual catalysis; kinetic isotope effects; oxa-Pictet–Spengler reaction; oxocarbenium ions.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Plausible mechanistic scenarios.
Figure 2.
Figure 2.
(A) Transition-state geometries for C–C bond-formation leading to the major (R) and minor (S) enantiomer of 3a. All distances are in angstroms (Å) and energies are in kcal/mol. Most hydrogen atoms have been removed for clarity. (B) Independent gradient model with Hirschfeld partitioning to visualize the numerous non-covalent interactions present in these systems. Green surfaces correspond to weak Van der Waal’s interactions present in the system. (C) Overlay of the catalysts fragments from TS leading to major and minor enantiomers.
Figure 3.
Figure 3.
Transition-state geometries for C–C bond-formation leading to all four diastereomers of 8a. All distances are in angstroms (Å) and energies are in kcal/mol. Most hydrogen atoms have been removed for clarity.
Scheme 1.
Scheme 1.
Catalytic Enantioselective Oxa-Pictet–Spengler Reactions
Scheme 2.
Scheme 2.
Structure–Activity/Selectivity Relationships
Scheme 3.
Scheme 3.
Studies Probing the Intermediacy of Oxocarbenium and Azafulvenium Ions
Scheme 4.
Scheme 4.
Scope of the Stereodivergent Reaction
Scheme 5.
Scheme 5.. Experimental 13C and 2H Kinetic Isotope Effects (KIEs) Determined for the Reaction of Tryptophol and Benzaldehyde Dimethyl Acetal Catalyzed by 1aa
aNumbers in parenthesis represent the 95% confidence range in the last digit of each KIE as determined from 12 measurements from two independent experiments. The first irreversible step and enantioselectivity-determining step in the catalytic cycle identified from the KIE experiments and density functional theory (DFT) calculations are also shown. Energies are Gibbs free energies relative to the oxocarbenium ion-catalyst prereactive complex.
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